Induction of CYP2C genes in human hepatocytes in primary culture.

Article Details

Citation

Gerbal-Chaloin S, Pascussi JM, Pichard-Garcia L, Daujat M, Waechter F, Fabre JM, Carrere N, Maurel P

Induction of CYP2C genes in human hepatocytes in primary culture.

Drug Metab Dispos. 2001 Mar;29(3):242-51.

PubMed ID
11181490 [ View in PubMed
]
Abstract

The expression and inducibility of four CYP2C genes, including CYP2C8, -2C9, -2C18, and -2C19, was investigated in primary cultures of human hepatocytes. By the use of RNase protection assay and specific antibodies, each CYP2C mRNA and protein were quantified unequivocally. The four CYP2C mRNAs were expressed in human livers and cultured primary hepatocytes, but only the CYP2C18 protein was not detected. Compounds known to activate the pregnane X receptor (PXR) such as rifampicin, or the constitutively activated receptor (CAR) such as phenobarbital, induced CYP2C8, CYP2C9, and to a lesser extent CYP2C19 mRNAs and proteins. CYP2C18 mRNA was expressed but not inducible. The concentration dependence of CYP2C8 and CYP2C9 mRNAs in response to rifampicin and phenobarbital paralleled that of CYP3A4 and CYP2B6, the maximum accumulation being reached with 10 microM rifampicin and 100 microM phenobarbital. In contrast, dexamethasone produced maximum induction of CYP2C8 and CYP2C9 mRNAs at 0.1 microM while in these conditions neither CYP3A4 nor CYP2B6 was significantly induced. Moreover, the concentration dependence of CYP2C8 and CYP2C9 mRNAs in response to dexamethasone paralleled that of tyrosine aminotransferase. Furthermore, dexamethasone, which has been recently shown to up-regulate PXR and CAR expression through the glucocorticoid receptor, potentiated CYP2C8 and CYP2C9 mRNA induction in response to rifampicin and phenobarbital. Collectively, these results suggest the possible implication of at least three receptors in the regulation of CYP2C8 and CYP2C9 expression, i.e., glucocorticoid receptor, PXR, and/or CAR.

DrugBank Data that Cites this Article

Drug Enzymes
DrugEnzymeKindOrganismPharmacological ActionActions
DexamethasoneCytochrome P450 2C8ProteinHumans
Unknown
Inducer
Details
Dexamethasone acetateCytochrome P450 2C8ProteinHumans
Unknown
Inducer
Details
PhenobarbitalCytochrome P450 2C18ProteinHumans
Unknown
Substrate
Details
PhenobarbitalCytochrome P450 2C8ProteinHumans
Unknown
Inducer
Details
RifampicinCytochrome P450 2C8ProteinHumans
Unknown
Inhibitor
Inducer
Details
SecobarbitalCytochrome P450 2C9ProteinHumans
Unknown
Inducer
Details
Drug Interactions
DrugsInteraction
Interactions
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